Lysine-Targeting Covalent Inhibitors

Angew Chem Int Ed Engl. 2017 Nov 27;56(48):15200-15209. doi: 10.1002/anie.201707630. Epub 2017 Oct 27.

Abstract

Targeted covalent inhibitors have gained widespread attention in drug discovery as a validated method to circumvent acquired resistance in oncology. This strategy exploits small-molecule/protein crystal structures to design tightly binding ligands with appropriately positioned electrophilic warheads. Whilst most focus has been on targeting binding-site cysteine residues, targeting nucleophilic lysine residues can also represent a viable approach to irreversible inhibition. However, owing to the basicity of the ϵ-amino group in lysine, this strategy generates a number of specific challenges. Herein, we review the key principles for inhibitor design, give historical examples, and present recent developments that demonstrate the potential of lysine targeting for future drug discovery.

Keywords: drug design; inhibitors; lysine; medicinal chemistry; structural biology.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't